Mechanisms and consequences of extrafollicular B cell activation during malaria

摘要 目前，对于为什么体液免疫不能有效地对抗疟疾，还缺乏机制上的理解。 以及为什么疟原虫感染是相关的免疫失败，即使在反复感染之后也是如此。我们的 长期目标是确定疟原虫，以及潜在的其他原生动物感染，如何共同选择和 颠覆体液免疫，这将有助于识别和开发新的免疫基础 针对疟疾等毁灭性疾病的干预措施。该项目的目标是定义机制 触发最初的体液免疫失调，并研究这些事件对形成的后果 持久的体液免疫记忆。我们的中心假设是强健的体液免疫不会形成 因为多克隆B细胞激活事件建立了损害新陈代谢的营养库， 疟原虫特异性记忆B细胞的转录和表观遗传编程及功能。其基本原理是 因为这个项目与我们最近的发现有关，即疟原虫感染会导致大量多克隆 B细胞的扩张，其功能是限制保护性记忆B细胞反应的营养吸收。删除 这些B细胞加速血液期疟原虫的清除并增强体液免疫 记忆。在感染小鼠的饮食中添加一种氨基酸足以克服营养 由这些B细胞施加的汇和代谢限制，并导致增强体液免疫记忆 回应。尽管我们有新的发现，但控制细胞激活和功能的分子机制 免疫抑制B细胞及其对记忆B细胞亲和力和寿命的影响仍然存在 在我们寻求提高对疟疾的体液免疫方面的关键知识差距。解决这些问题的两个目标 优先问题。在第一个目标中，我们将确定支配细胞的分子和细胞机制 扩增这些免疫抑制B细胞，并调查这些群体是否与其他 与体液免疫失调相关的感染。在第二个目标中，我们将研究分子 以及免疫抑制B细胞扩增对遗传和表观遗传编程的细胞影响 记忆B细胞的数量。我们已经开发了几种创新的新试剂，能够提供前所未有的分辨率 用于抗疟疾体液免疫的研究。这个项目的意义与我们的新发现直接相关 表明在疟原虫感染过程中发生的病理生理变化会持久地影响B细胞的命运 和功能。因此，确定这些途径如何协调调节多克隆B细胞的激活， 发展和体液免疫对研究传染病免疫学的人将具有广泛的重要性。 和疫苗学。

ABSTRACT There is currently a lack of mechanistic understanding of why humoral immunity against malaria is not efficiently induced and why Plasmodium infections are associated immune failures, even following repeated infections. Our long-term goal is to determine how Plasmodium parasites, and potentially other protozoan infections, co-opt and subvert humoral immunity, which will help with the identification and development of new immune-based interventions against devastating diseases like malaria. The objectives of this project are to define mechanisms that trigger initial humoral immune dysregulation and study the consequences of these events on the formation of durable humoral immune memory. Our central hypothesis is that robust humoral immunity does not develop efficiently because polyclonal B cell activation events establish a nutrient sink that impairs the metabolic, transcriptional and epigenetic programming and function of Plasmodium-specific memory B cells. The rationale for this project is linked to our recent discovery that Plasmodium infection results in a massive polyclonal expansion of B cells that function as a nutrient sink that limits protective memory B cell responses. Deletion of these B cells accelerates blood-stage Plasmodium parasite clearance and enhances humoral immune memory. Supplementing the diet of infected mice with a single amino acid is sufficient to overcome the nutrient sink and metabolic constraints imposed by these B cells and results in enhanced humoral immune memory responses. Despite our new findings, the molecular mechanisms governing the activation and function of immunoinhibitory B cells and the impact of these cells on the affinity and longevity of memory B cells remain critical knowledge gaps in our quest to improve humoral immunity against malaria. Two Aims address these priority questions. In the first Aim we will determine the molecular and cellular mechanisms that govern the expansion of these immunosuppressive B cells and investigate whether these populations are relevant to other infections associated with dysregulated humoral immunity. In the second Aim we will investigate the molecular and cellular consequences of immunosuppressive B cell expansions on the genetic and epigenetic programming of memory B cells. We have developed several innovative new reagents that afford unprecedented resolution for the study anti-malarial humoral immunity. The significance of this project is directly linked to our new findings showing that pathophysiological changes that occur during Plasmodium infection durably imprints on B cell fate and function. Thus, determining how these pathways coordinately regulate polyclonal B cell activation, development and humoral immunity will be broadly important to those studying infectious disease immunology and vaccinology.